Abstract Systemic lupus erythematosus (SLE, lupus) is an autoimmune disease that causes systemic inflammation and tissue damage. Up to 60% of SLE patients develop kidney involvement (lupus nephritis), and 10-30% progress to end-stage renal disease (ESRD) within 10 years of diagnosis and despite treatment. Mortality in SLE ESRD is four-fold higher than in SLE with lupus nephritis alone, and twice as high as mortality in non-SLE ESRD, even though SLE patients are significantly younger at ESRD onset. Although numerous studies demonstrate poor outcomes, strategies to improve them have not been developed. Hydroxychloroquine use in SLE without ESRD has been associated with lower rates of SLE flares and thrombotic complications, as well as better overall survival. To date, there are no clinical studies exploring the benefits of hydroxychloroquine in SLE ESRD. Studying the effects of this drug directly in ESRD patients is important to develop individualized treatments and to decrease mortality. Our guiding hypothesis is that hydroxychloroquine use will decrease morbidity and mortality in SLE patients with ESRD undergoing the two most common renal replacement modalities, hemodialysis and kidney transplantation. To investigate this hypothesis we will analyze data from the NIH-sponsored US Renal Database Systems (USRDS), a US-wide registry of ESRD patients that includes 5,000 incident SLE patients enrolled over 5 years. Using USRDS data in Aims 1 and 2 provides a cost-effective and efficient way to study large numbers of SLE patients with ESRD that present well-defined outcomes. Additionally, we will prospectively collect SLE-specific longitudinal data not available in the USRDS The clinical investigation will be carried out at the Albert Einstein College of Medicine and the New York University School of Medicine under the mentorship of three senior investigators in SLE, outcomes research, and biostatistics. This project addresses an understudied and clinically important area. The specific aims are a significant extension of Dr. Broder?s previous retrospective work showing that hydroxychloroquine use is associated with lower mortality in SLE with ESRD. This project is essential groundwork for an interventional study. The multidisciplinary mentoring team and career development activities will enable Dr. Broder develop expertise in the following clinical and translational areas outlined in the NIH Lupus Research Action Plan: analysis of large scale databases; comparative effectiveness; individualized drug therapies; and innovative trial designs.